Aralkyl-tetrahydro-pyridines, their preparation and pharmaceutical compositions containing same

ABSTRACT

The present invention relates to compounds of formula (I): 
                         
in which
         X represents N or CH; R 1  represents a hydrogen or halogen atom or a CF 3  group; n is an integer from 1 to 5; A represents a partially saturated carbonaceous bi- or tricycle; it also relates to their salts, solvates, N-oxides, the pharmaceutical compositions containing them, a method for their preparation and synthesis intermediates in this method.

The present invention relates to novel aralkyltetrahydropyridines, thepharmaceutical compositions containing them, a method for theirpreparation and synthesis intermediates in this method.

EP 0 458 697 describes naphthylalkyltetrahydropyridine derivativeshaving an intestinal motility modulating activity.

Bourrié et al. (Proc. Natl. Acad. Sci. 1999, 96(22):12855-12859) havedescribed the activity of a compound called SR 57746(1-(2-naphth-2-ylethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine)in an experimental autoimmune encephalomyelitis (EAE) model and in themodulation of TNF-alpha (Tumor Necrosis Factor).

It has now been found that some tetrahydropyridines, substituted with apartially saturated aralkyl radical, possess a potent activity on themodulation of TNF-alpha.

TNF-alpha is a cytokine which has recently aroused interest as amediator of immunity, of inflammation, of cell proliferation, offibrosis, etc. This mediator is present in abundance in inflamedsynovial tissue and exercises an important role in the pathogenesis ofautoimmunity (Annu. Rep. Med. Chem., 1997, 32:241-250).

Thus, the present invention relates, according to one of its aspects, toaralkyltetrahydropyridines of formula (I):

in which

-   X represents N or CH;-   R₁ represents a hydrogen or halogen atom or a CF₃ group;-   n is an integer from 1 to 5;-   A represents a group of formula (a) to (d):

in which m is 1 or 2;

and their salts or solvates and their N-oxides.

In the present description, the term “halogen” denotes an atom chosenfrom chlorine, bromine, iodine and fluorine.

Preferred compounds are those where n is 1.

Other preferred compounds are those where R₁ is a CF₃ group.

Other preferred compounds are those where X is CH and R₁ is at the3-position of the benzene.

Other preferred compounds are those where X is CH and R₁ is a CF₃ group.

Other preferred compounds are those where X is N and pyridine issubstituted at the 2,6-positions.

The salts of the compounds of formula (I) according to the presentinvention comprise both the addition salts with pharmaceuticallyacceptable inorganic or organic acids such as the hydrochloride,hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate,maleate, tartrate, fumarate, gluconate, methanesulfonate,2-naphthalenesulfonate, etc., and the addition salts which allow asuitable separation or crystallization of the compounds of formula (I),such as the picrate or oxalate, or the addition salts with opticallyactive acids, for example camphorsulfonic acids and mandelic acids orsubstituted mandelic acids.

According to the present invention, the compounds of formula (I) mayexist as N-oxide derivatives, in particular they may bear an N-oxidegroup on the tetrahydropyridine.

The compounds of formula (I) can be synthesized by a method whichinvolves

-   (a) reacting the compound of formula (II):

-    in which R₁ is as defined above, with the acid of formula (III) or    one of its functional derivatives:

-   -   in which n and A are as defined above,

-   (b) reducing the carbonyl group of the compound of formula (IV) thus    obtained:

-   (c) dehydrating the intermediate piperidinol of formula (V) thus    obtained

-   (d) isolating the compound of formula (I) thus obtained and    optionally converting it to one of its salts or solvates or to its    N-oxide derivatives.

The reaction of step (a) can be suitably carried out in an organicsolvent at a temperature of between −10° C. and the reflux temperatureof the reaction mixture.

It may be preferable to carry out the reaction at cold temperature whenit is exothermic, as in the case where the chloride is used asfunctional derivative of the acid of formula (III).

As compound of formula (III), it is possible to use either the freeacid, optionally activated (for example with BOP, namelytri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate),or one of its functional derivatives such as, for example, an anhydride,a mixed anhydride, an active ester or an acid halide, preferably thebromide. Among the active esters, p-nitrophenyl ester is particularlypreferred, but methoxyphenyl, trityl and benzhydryl esters, and thelike, are also suitable.

As reaction solvent, a halogenated solvent such as methylene chloride,dichloroethane, 1,1,1-trichloroethane, chloroform or the like, ispreferably used, but other organic solvents compatible with the reagentsused, for example dioxane, tetrahydrofuran or a hydrocarbon such ashexane, may also be used.

The reaction may be suitably carried out in the presence of a protonacceptor, for example an alkali metal carbonate or a tertiary amine suchas triethylamine.

The reduction of step (b) may be suitably carried out by appropriatereducing agents such as borane complexes, for example borane-dimethylsulfide ([CH₃]₂S—BH₃), aluminum hydrides or a lithium aluminum hydridecomplex in an inert organic solvent, at a temperature of between 0° C.and the reflux temperature of the reaction mixture, according to thecustomary techniques.

The expression “inert organic solvent” is understood to mean a solventwhich does not interfere with the reaction. Such solvents are forexample ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or1,2-dimethoxyethane.

According to a preferred mode of operation, the procedure is carried outwith the borane-dimethyl sulfide used in excess in relation to thestarting compound (II), at the reflux temperature, optionally under aninert atmosphere. The reduction is normally complete after a few hours.

The dehydration of step (c) is easily carried out, for example, using anacetic acid/sulfuric acid mixture, at a temperature of between roomtemperature and the reflux temperature of the solvent used.

According to a preferred method, the reaction of step (c) is carried outin an acetic acid/sulfuric acid mixture in a 3/1 ratio by volume, byheating at the temperature of about 80-100° C. for 1 to 3 hours.

The desired compound is isolated according to conventional techniques inthe form of a free base or of one of its salts. The free base may beconverted to one of its salts by mere salification in an organic solventsuch as an alcohol, preferably ethanol or 2-propanol, an ether such as1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon such ashexane.

The compound of formula (I) obtained is optionally converted to one ofits N-oxide derivatives.

The compounds of formula (I) bearing an N-oxide group on the nitrogenatom of the tetrahydropyridine can be prepared by oxidation of thecorresponding compound of formula (I). In this case, the compound offormula (I) is subjected to an oxidation reaction according toconventional methods, for example to a reaction with m-chloroperbenzoicacid in a suitable solvent, and isolated according to the usualtechniques well known to persons skilled in the art.

The compounds of formula (I) can also be prepared by a condensationreaction from a tetrahydropyridine of formula (VI):

in which X and R₁ are as defined above, with a compound of formula(VII):

in which n and A are as defined above, and L is a leaving group,isolation of the compound of formula (I) thus obtained and optionalconversion to one of its salts or solvates.

As leaving group “L”, it is possible for example to use a halogen group,or any other group suitable for condensation with the compound offormula (VI).

The condensation reaction is carried out by mixing the startingcompounds (VI) and (VII) in an organic solvent such as an alcohol suchas for example methanol or butanol, in the presence of a base such asfor example alkali metal carbonates, at a temperature of between roomtemperature and the reflux temperature of the chosen solvent, accordingto conventional methods.

The starting compounds of formula (II) are known or they can be preparedin a similar manner to the known compounds.

The compounds of formula (III°)

in which A° is a group of formula (a), (c) or (d) as defined above, n isan integer from 1 to 5 and m is 1 or 2, and their salts or solvates arenovel compounds and constitute a subsequent aspect of the presentinvention.

When A is a group (a), these novel compounds are represented by formula(III′)

where n and m are as defined above, and may be synthesized by a methodwhich involves:

-   -   (i) reacting compound (VIII) below

-   -    where m is 1 or 2, with a dialkyl carbonate in the presence of        a strong base such as an alkali metal hydride,    -   (ii) reacting the compound of formula (IX) thus obtained

-   -    with a Hal-(CH₂)_(n)—COOAlk derivative in which n is as defined        above, Alk is an alkyl group and Hal is a halogen atom, in the        presence of a strong base such as an alkali metal hydride,    -   (iii) hydrolyzing and decarboxylating the compound (X) thus        obtained

-   -    by heating in the presence of a base, such as sodium hydroxide,    -   (iv) reducing the ketone of formula (XI) thus obtained

-   -   (v) aromatizing the compound of formula (XII) thus obtained

-   -    for example by oxidation with Pd/C at high temperature, in a        solvent such as Decalin, obtaining the compound of formula        (III′) which is isolated according to conventional methods and        optionally converted to one of its salts.

When A is a group (c), these novel compounds are represented by formula(III″)

where n and m are as defined above.

When n is 0, these compounds may be synthesized according to a methodwhich involves:

-   -   (vi) reacting the compound of formula (XIII)

-   -    with polyphosphoric acid (PPA) and reducing the 9-oxofluorene        derivative thus obtained, obtaining the compound of formula        (III″) where n is 0; and when n is 1,    -   (vii) esterifying and reducing the fluorenecarboxylic acid (XIV)        thus obtained:

-   -    for example by reaction with methanol in the presence of        hydrochloric acid followed by reduction with LiAlH₄    -   (viii) converting the alcohol of formula (XV) thus obtained

-   -    to a cyano derivative, for example by preparation of the        corresponding chloride and reaction with KCN;    -   (ix) and hydrolyzing this cyano derivative of formula (XVI)

-   -    for example in an acid medium, obtaining the compound of        formula (III″) where n is 1, which is isolated according to        conventional methods and optionally converted to one of its        salts.

If it is desired to prepare the compounds of formula (III″) where nis >1, it is sufficient to repeat the passages (vii)-(ix), althoughother known methods of synthesis may be used to extend the alkyl chain.

When A is a group (d), these novel compounds are represented by formula(III′″)

where n and m are as defined above.

The compounds of formula (III′″) where n is 0 or 1, may be synthesizedaccording to a method which involves:

-   -   (x) reacting the compound of formula (XVII)

-   -    with (1-cyano-3,3-diethoxypropyl)diethyl phosphonate;    -   (xi) cyclizing the compound of formula (XVIII) thus obtained:

-   -    for example in the presence of SnCl₄, and    -   (xii) either hydrolyzing the cyano derivative of formula (XIX)

-   -    obtaining the compound of formula (III′″) where n is 0,    -   (xiii) or, when n is 1, converting the derivative of        formula (XIX) to a ketone of formula (XX)

-   -    for example by a Grignard reaction with CH₃MgI; and    -   (xiv) converting the ketone (XX) to the corresponding acid of        formula (III′″) where n is 1.

If it is desired to prepare the compounds of formula (III′″) where nis >1, it is sufficient to repeat the passages (vii)-(ix) above startingwith the acid of formula (III′″) as obtained in the passage (xiv), or touse other methods of synthesis known to extend the alkyl chain.

When the cyclization of the passage (xi) is carried out starting with abeta-aldehyde, it is possible to obtain two derivatives of formula(XIX), because the formation of the aromatic ring may be achieved bycyclization on one of the two adjacent positions. In this case, theisomers thus formed should be separated, for example by means ofchromatography on a silica gel column, and proceeding using the desiredisomer.

The reactions described above are in general well known to personsskilled in the art. Detailed examples of such methods are in any casereported in the experimental section.

The compounds of the invention have advantageous properties with respectto the inhibition of TNF-α.

These properties were demonstrated with the aid of a test aimed atmeasuring the effect of molecules on the synthesis of TNF-α induced inBalb/c mice by lipopolysaccharide (LPS) from Escherichia Coli (055:B5,Sigma, St. Louis, Mo.).

The test products are administered orally to groups of 5 female 7- to8-week old Balb/c mice (Charles River, France). One hour later, the LPSis administered intravenously (10 μg/mouse). The blood of each animal istaken 1.5 hours after the administration of the LPS. The samples arecentrifuged and the plasma is recovered and frozen at −80° C. The TNF-αis measured using commercial kits (R and D, Abingdon, UK).

In this test, representative compounds of the invention were found to bevery active, by inhibiting the synthesis of TNF-α even at very lowdoses.

By virtue of this activity and their low toxicity, the compounds offormula (I) and their salts or solvates can be used in the treatment ofdiseases linked to immune and inflammatory disorders or as analgesics.In particular, the compounds of formula (I) can be used for treatingatherosclerosis, autoimmune diseases, diseases entailing demyelinizationof the neurons (such as multiple sclerosis), asthma, rheumatoidarthritis, fibrotic diseases, pulmonary idiopathic fibrosis, cysticfibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis,gout, bone and cartilage resorption, osteoporosis, Paget's disease,multiple myeloma, uveoretinitis, septic shock, septicemia, endotoxicshock, graft-versus-host reaction, graft rejection, adult respiratorydistress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn'sdisease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer'sdisease, Parkinson's disease, disseminated lupus erythematosus,hemodynamic shock, ischemic pathologies (myocardial infarction,myocardial ischemia, coronary vasospasm, angina pectoris, cardiacinsufficiency, heart attack), post-ischemic reinfusion attacks, malaria,mycobacterial infections, meningitis, leprosy, viral infections (HIV,cytomegalovirus, herpesvirus), opportunistic infections associated withAIDS, tuberculosis, psoriasis, atopic dermatitis and contact dermatitis,diabetes, cachexia, cancer and radiation-mediated damage.

The compounds of formula (I) and the pharmaceutically acceptable saltsand solvates thereof are preferably administered orally.

In the pharmaceutical compositions of the present invention for oraluse, the active principle can be administered in unit administrationforms, as a mixture with conventional pharmaceutical supports, toanimals and human beings for the treatment of the abovementionedcomplaints. The appropriate unit administration forms comprise, forexample, tablets, which may be splittable, gel capsules, powders,granules and oral solutions or suspensions.

When a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose or other suitable materialsor alternatively they can be treated such that they have sustained ordelayed activity and such that they release a predetermined amount ofactive principle continuously.

A preparation in the form of gel capsules is obtained by mixing theactive ingredient with a diluent and pouring the mixture obtained intosoft or hard gel capsules.

A preparation in the form of syrup or elixir can contain the activeingredient together with a sweetener, preferably a calorie-freesweetener, methylparaben and propyl paraben as antiseptic agents, aswell as a flavoring and a suitable colorant.

The water-dispersible powders or granules can contain the activeingredient as a mixture with dispersants or wetting agents, orsuspending agents, such as polyvinylpyrrolidone, as well as withsweeteners or flavour enhancers.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more supports or additives.

In the pharmaceutical compositions according to the present invention,the active principle can also be in the form of an inclusion complex incyclodextrins, or ethers or esters thereof.

The amount of active principle to be administered depends, as always, onthe degree of progress of the disease as well as the age and weight ofthe patient. Nevertheless, the unit doses generally comprise from 0.001mg to 100 mg, better still from 0.01 mg to 50 mg and preferably from 0.1mg to 20 mg of active principle, advantageously from 0.5 mg to 10 mg.

According to another of its aspects, the present invention relates to acombination comprising a compound of formula (I) or one of itspharmaceutically acceptable salts or solvates, and at least one compoundchosen from immunosuppressants, such as interferon beta-1b;adrenocorticotropic hormone; glucocorticoids such as prednisone ormethylprednisolone; interleukin-1 inhibitors.

More particularly, the invention relates to a combination comprising acompound of formula (I), or one of its pharmaceutically acceptable saltsor solvates, and at least one compound chosen from roquinimex(1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinolinecarboxanilide),myloran (product from the company Autoimmune containing bovine myelin),antegren (monoclonal human antibody from the companies Elan/AthenaNeurosciences) and recombinant interferon beta-1b.

Other possible combinations are those consisting of a compound offormula (I), or one of its pharmaceutically acceptable salts orsolvates, and a potassium-channel blocker such as, for example,fampridine (4-aminopyridine).

According to another of its aspects, the invention relates to a methodfor treating diseases linked to immune and inflammatory disorders aswell as in the treatment of pain, in particular atherosclerosis,autoimmune diseases, diseases entailing demyelinization of the neurons(such as multiple sclerosis), asthma, rheumatoid arthritis, fibroticdiseases, pulmonary idiopathic fibrosis, cystic fibrosis,glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, boneand cartilage resorption, osteoporosis, Paget's disease, multiplemyeloma, uveoretinitis, septic shock, septicemia, endotoxic shock,graft-versus-host reaction, graft rejection, adult respiratory distresssyndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease,ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease,Parkinson's disease, disseminated lupus erythematosus, hemodynamicshock, ischemic pathologies (myocardial infarction, myocardial ischemia,coronary vasospasm, angina pectoris, cardiac insufficiency, heartattack), post-ischemic reinfusion attacks, malaria, mycobacterialinfections, meningitis, leprosy, viral infections (HIV, cytomegalovirus,herpesvirus), opportunistic infections associated with AIDS,tuberculosis, psoriasis, atopic dermatitis and contact dermatitis,diabetes, cachexia, cancer and radiation-mediated damage, comprising theadministration of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, alone or in combination with otheractive principles.

The examples which follow illustrate the invention.

Preparation 1 1,2,3,6,7,8-Hexahydro-5H-cyclopenta[b]naphthalen-5-one

A suspension of 61 g (0.457 mol) of anhydrous AlCl₃ in 188 ml of adichloromethane/nitromethane=8/1 mixture is cooled to 0-5° C. and 22.15g of indan and, in portions, 22.5 g (0.225 mol) of succinic anhydrideare added thereto. After one hour at 0° C., the medium is poured into awater/ice mixture, hydrochloric acid at 37% is added until a clearsolution is obtained. The medium is extracted with ethyl acetate, washedwith water, the organic phase is dried and the solvent is evaporated offunder reduced pressure. A white solid is obtained which is dissolved in500 ml of dioxane. 4.6 ml of sulfuric acid at 98% in 50 ml of ethanoland 3.6 g of 10% Pd/C are added thereto. After 5 hours under a hydrogenatmosphere, the catalyst is filtered off, the solvent is evaporated off,the residue is taken up in water and the medium is extracted with ethylacetate. The product obtained is dissolved in 20 ml of methanol and 8 mlof a 1 N aqueous sodium hydroxide solution are added thereto and themedium is stirred at room temperature for 2 hours. The solvent isevaporated off, water is added, the medium is brought to an acidic pH,it is extracted and a white solid is isolated. 38.7 g of this productare dissolved in 1000 ml of anhydrous methylene chloride under anitrogen atmosphere; the medium is cooled to 0° C. and 47 g (0.225 mol)of PCl₃ are carefully added thereto, the medium is stirred at 0° C. fortwo hours and 121.8 g (0.467 mol) of SnCl₄ are slowly added thereto and,after 10 minutes, the medium is allowed to heat up to room temperature.After two hours at room temperature, the medium is poured into awater/ice mixture, extracted with methylene chloride and an oil isisolated which is then purified by chromatography on a silica gelcolumn, eluting with a cyclohexane/ethyl acetate=8/2 mixture. 6.0 g ofthe title compound are obtained.

Preparation 2 2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-ylacetic acid

The procedure being carried out under a nitrogen stream, 3 g of sodiumhydride at 80% (0.075 mol) are mixed in 845 ml of tetrahydrofuran and0.7 g (0.0375 mol) of the product of Preparation 1, dissolved in 45 mlof tetrahydrofuran, is added thereto. After 1 hour under reflux, 9 ml(0.075 mol) of diethyl carbonate in 45 ml of tetrahydrofuran are addedand the medium is kept stirring under reflux for 5 hours. The mixture iscooled and a saturated aqueous ammonium chloride solution and water areadded thereto until complete dissolution is obtained and the medium isextracted with ethyl acetate. The medium is washed with water, theorganic phase is dried and the solvent is evaporated off under reducedpressure. The oil obtained is dissolved in 60 ml of tetrahydrofuran andthis solution is added, at room temperature and under a nitrogenatmosphere, to a suspension of sodium hydride at 80% (1.6 g; 0.41 mol)in 30 ml of tetrahydrofuran. The medium is stirred for 30 minutes and8.8 ml of ethyl bromoacetate (0.08 mol) are added thereto, and themedium is stirred at room temperature for 5 hours. Ammonium chloride isadded and the medium is extracted with methylene chloride. The medium iswashed with water, the organic phase is dried and the solvent isevaporated off under reduced pressure. The oil thus obtained isdissolved in 600 ml of a 0.5 N aqueous-alcoholic solution of sodiumhydroxide (EtOH/H₂O ratio=2/1). The medium is heated at about 40° C.until complete conversion of the product to its sodium salt is obtained(formation of a product with the base in the thin-layer chromatographytrial, eluting with an ethyl acetate/hexane=3/7 mixture. After about 8hours, half of the solvent is evaporated off under reduced pressure, themedium is acidified with 15 ml of 1 N hydrochloric acid and heated at50° C. for about 45 minutes. The medium is extracted with ethyl acetate,the organic phase is dried and the solvent is evaporated off underreduced pressure. The product obtained is dissolved in 60 ml of aceticacid and 4.5 ml of sulfuric acid at 98%, diluted in 9 ml of acetic acid,and 1 g of 10% Pd/C are added thereto; the medium is then hydrogenatedfor 8 hours. Half of the solvent is evaporated off, the catalyst isfiltered off, water is added and the medium is extracted with ethylacetate, the organic phase is dried and the solvent is evaporated off.The product thus obtained is dissolved in 100 ml of methanol, 200 mg ofpara-toluenesulfonic acid are added thereto and the medium is heatedunder reflux for 4 hours. The solvent is partially evaporated off and 50ml of a 5% aqueous sodium bicarbonate solution are added thereto and themedium is extracted with diethyl ether, the medium is washed with waterand with brine. The organic phase is dried, and the solvent isevaporated off under reduced pressure. The product thus obtained isdissolved in Decalin (20 ml), 1.4 g of 10% Pd/C are added thereto andthe medium is heated at 200° C. for 48 hours. The catalyst is filteredoff, the solvent is evaporated off and the crude reaction product ispurified by chromatography on a silica gel column, eluting with acyclohexane/ethyl acetate=9/1 mixture. 750 mg of the product thusobtained are dissolved in 30 ml of ethanol, 20 ml of 1 N NaOH are addedthereto and the medium is heated at 50° C. for 4 hours. The ethanol isevaporated off and the medium is acidified with 1 N HCl. A white solidis obtained.

m.p. 185-188° C.

Preparation 3 5-(2-Bromoethyl)indan

2 ml (0.016 mol) of indan in 33 ml of methylene chloride and 1.6 ml(0.019 mol) of bromoacetyl bromide are mixed at 0° C. 2.27 g (0.017 mol)of AlCl₃ are slowly added and the medium is allowed to return to roomtemperature and stirred for 2 hours. The mixture is poured intowater/ice and extracted with methylene chloride. The organic phase isdried, filtered and the solvent is evaporated off under reducedpressure. The crude reaction product is crystallized from hexane. Awhite solid is separated (m.p. 57.8-58.1° C.) corresponding to theacylation product. 1.67 g (7 mmol) of this product are dissolved in 3.9ml of triethylsilane and 3.9 ml of trifluoroacetic acid and the mediumis heated at 80° C. for two hours. The medium is poured into an ice/NaOHmixture and extracted with ethyl acetate. The title compound isobtained.

Preparation 4 2-(2-Bromoethyl)-5,6,7,8-tetrahydronaphthalene

By carrying out the procedure as described in Preparation 3, but usingTetralin instead of indan, the title compound is obtained.

Preparation 5 5-(3-Bromopropyl)indan

By carrying out the procedure as described in Preparation 3 but usingbromopropionyl bromide instead of bromoacetyl bromide, the titlecompound is obtained.

Preparation 6 5-(3-Bromobutyl)indan

By carrying out the procedure as described in Preparation 3 but usingbromobutanoyl bromide instead of bromoacetyl bromide, the title compoundis obtained.

Preparation 7 2-(2-Bromoethyl)fluorene

By carrying out the procedure as described in Preparation 3 but usingfluorine instead of indan, the title compound is obtained.

Preparation 8 2-(2-Bromoethyl)-9,10-dihydrophenanthrene

By carrying out the procedure as described in Preparation 3 but using9,10-dihydrophenanthrene instead of indan, the title compound isobtained.

Preparation 9 3-Fluorenylacetic acid 9a) 9-Oxofluoren-3-ylcarboxylicacid

A mixture of 0.45 g (0.00186 mol) of 2,5-biphenyldicarboxylic acid and13.9 g of polyphosphoric acid (PPA) is heated to 200° C. After one hour,the medium is cooled to 100° C. and ice is added thereto until a volumeof about 100 ml is obtained. The medium is filtered and a solution of0.5 g of NaOH in 90 ml of water is added to the precipitate and themedium is stirred for one hour at 60° C. The medium is acidified withhydrochloric acid and extracted with ethyl acetate. The organic phase isdried, filtered and the solvent is evaporated off under reducedpressure. 0.31 g of the title product is obtained in the form of a lightbrown solid.

9b) Fluoren-3-ylcarboxylic acid

0.27 g (0.0012 mol) of the product of the preceding step is dissolved in2.5 ml of ethylene glycol and 0.1 g of NaOH and 0.25 ml of hydrazine at98% (d=1.03) are added thereto. The medium is heated under reflux for1.5 hours, it is allowed to return to room temperature, 70 ml of waterare added and the medium is acidified to pH=6 with hydrochloric acid.The medium is extracted with ethyl acetate, the organic phase is dried,filtered and the solvent is evaporated off under reduced pressure. 0.4 gof the title product is thus obtained in the form of a yellow solid.

9c) Methyl ester of fluoren-3-ylcarboxylic acid

The ester of the product of the preceding step is prepared with the aidof methanol in hydrochloric acid. The solution is brought to a basic pHand extracted with ethyl acetate, thus obtaining the title product inthe form of an oil.

9d) 3-Hydroxymethylfluorene

A mixture of 0.68 g of LiAlH₄ in 7 ml of anhydrous ethyl ether is cooledto 0° C. and under a nitrogen stream, and a solution of 3.4 g (0.0152)of the product of the preceding step in 27 ml of anhydrous ethyl etherare added thereto dropwise and the medium is stirred overnight. Awater/ice mixture is then added, the medium is extracted with ethylacetate, the organic phase is dried, filtered and the solvent isevaporated off under reduced pressure. 3 g of the crude product are thusobtained, which product is purified by chromatography on a silica gelcolumn, eluting with a cyclohexane/ethyl acetate 7/3 mixture. 1.33 g ofthe title product are thus obtained in the form of a white solid.

9e) 3-Chloromethylfluorene

A solution of 35 mg (0.178 mmol) of the product of the preceding step in0.5 ml of methylene chloride is cooled to 0° C. and 0.13 ml of thionylchloride (1.178 mmol) is added thereto dropwise. The mixture is stirredfor three hours at room temperature and a mixture of water and sodiumbicarbonate is added thereto to pH 8. The medium is extracted withmethylene chloride, the organic phase is dried, filtered and the solventis evaporated off under reduced pressure. 20 mg of the title product arethus obtained in the form of a yellow oil.

9f) 3-Cyanomethylfluorene

1.3 g (0.00605 g) of the product of the preceding step are dissolved in32 ml of DMSO and 0.44 g (0.00666 mol) of KCN is added thereto. Themedium is heated at 80° C. for 3 hours, a water/ice mixture is addedthereto and the medium is extracted with ethyl acetate. The organicphase is dried, filtered and the solvent is evaporated off under reducedpressure. The crude product is purified by flash chromatography, elutingwith a cyclohexane/ethyl acetate 8/2 mixture. 250 mg of the titleproduct are thus obtained.

9g) 3-Fluorenylacetic acid

The cyano derivative of the preceding step is hydrolyzed with the aid of6 N hydrochloric acid while heating under reflux. A water/ice mixture isadded and the medium is extracted with ethyl acetate. The organic phaseis dried, filtered and the solvent evaporated off under reducedpressure. 0.22 g of the title product is thus obtained in the form of asolid.

m.p.: 166-168° C.

Preparation 10 2,3-Dihydro-1H-cyclopenta[a]naphthalen-8-ylacetic acid10a) 4,4-Diethoxy-2-indan-4-ylmethylenbutyronitrile

0.23 g (0.0092 mol) of NaH at 60% in 20 ml of anhydrous THF is cooled at0° C. under a nitrogen stream and a solution of 2.26 g (0.0085 mol) of adiethyl ester of (1-cyano-3,3-diethoxypropyl)phosphonic acid in 16 ml ofTHF is added thereto. After 30 minutes, the mixture becomes clear and asolution of 1.1 g (0.0075 mol) of 2,3-dihydro-1H-inden-8-ylbenzaldehydein 16 ml of THF is then added thereto dropwise. The medium is stirredfor one hour at 0° C. and a water/ice mixture is added. The medium isextracted with methylene chloride, the organic phase is washed with anNaOH/water solution, the organic phase is dried, filtered and thesolvent is evaporated off under reduced pressure. 2.49 g of the crudeproduct are thus obtained in the form of an orange-colored oil which ispurified by flash chromatography, eluting with a cyclohexane/ethylacetate 95/5 mixture. The title product is thus obtained.

10b) 8-Cyano-2,3-dihydro-1H-cyclopenta[a]naphthalene

A mixture of 0.56 g (0.0021 mol) of the product of the preceding step in14 ml of methylene chloride is cooled to 0° C. and 152 ml (0.0013 mol)of SnCl₄ (d=2.226) are added thereto dropwise. The medium is stirred atroom temperature for 4 hours, sodium bicarbonate at 10% is then addedthereto and the medium is extracted with methylene chloride. The organicphase is dried, filtered and the solvent is evaporated off under reducedpressure. 0.43 g of the title product is thus obtained in the form of alight yellow solid.

10c) 8-Methylcarbonyl-2,3-dihydro-1H-cyclopenta[a]naphthalene

0.5 g (0.0025 mol) of the product of the preceding step is dissolved in20 ml of anhydrous toluene and 1.6 ml (0.005 mol) of 3 M methylmagnesiumiodide are added thereto dropwise and under a nitrogen stream. Themedium is stirred overnight at room temperature, and water andhydrochloric acid are then added thereto. The medium is stirred for 15minutes, brought to a basic pH with a 5 M NaOH solution and extractedwith ethyl acetate. The organic phase is washed, it is dried, filteredand the solvent is evaporated off under reduced pressure. 0.69 g of thecrude product is thus obtained, which product is purified by flashchromatography, eluting with a hexane/diethyl ether 95/5 mixture. 0.35 gof the title product is thus obtained.

10d) 8-(Morpholinothiocarbonyl)-2,3-dihydro-1H-cyclopenta[a]naphthalene

0.35 g (0.0016 mol) of the product of the preceding step is dissolved in0.35 ml (0.0016 mmol) of morpholine (d=0.999) and 0.54 g (0.0020) ofsulfur and a crystal of para-toluenesulfonic acid (PTSA) are addedthereto. The medium is heated under reflux for 6 hours and methanol isthen added. The medium is stirred at room temperature overnight. Thesolvent is removed under reduced pressure and 2.5 g of the crude productare thus obtained, which product is purified by flash chromatography,eluting with a cyclohexane/ethyl acetate 9/1 mixture. 0.16 g of thetitle product is thus obtained.

10e) 2,3-Dihydro-1H-cyclopenta[a]naphthalen-8-ylacetic acid

0.16 g (0.0005 mol) of the product of the preceding step is dissolved in7.6 ml of a 1:1 methanol/water solution and 0.02 g of solid NaH is addedthereto. The medium is heated under reflux for 6 hours, the solvent isthen removed under reduced pressure, the residue is taken up in a waterand ethyl acetate mixture, the organic phase is removed, the aqueousphase is acidified and extracted with methylene chloride. The organicphase is dried, filtered and the solvent evaporated off under reducedpressure. 20 mg of the title product are thus obtained.

Preparation 11 5,6,7,8-Tetrahydrophenanthren-3-ylacetic acid

By following the procedure described in Preparation 10 but using5,6,7,8-tetrahydronaphthalen-1-ylbenzaldehyde instead of2,3-dihydro-1H-inden-7-ylbenzaldehyde, the title product is obtained.

Preparation 12 5,6,7,8-Tetrahydroanthren-2-ylacetic acid

By following the procedure described in Preparation 10 but using5,6,7,8-tetrahydronaphthalen-2-ylbenzaldehyde instead of2,3-dihydro-1H-inden-7-ylbenzaldehyde, the title product is obtained.

EXAMPLE 11-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-[3-trifluoromethylphenyl]-1,2,3,6-tetrahydropyridineand its hydrochloride

1a)1-[4-Hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]-2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)-1-ethanone

400 mg (1.76 mol) of the product of Preparation 2 are dissolved under anitrogen atmosphere in 10 ml of anhydrous methylene chloride and 430 mg(1.76 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 0.79 g(1.76 mol) of BOP and 0.73 ml of triethylamine are added thereto and themedium is stirred at room temperature for 3 hours. 40 ml of ethylacetate are added, the medium is washed with a 1 N hydrochloric acidsolution, then with a 1 N sodium hydroxide solution, and then withwater. The organic phase is dried over sodium sulfate and the solvent isevaporated off. 0.8 g of the title compound is obtained in the form ofan oil.

1b)1-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The product obtained in Example 1a is dissolved in 7 ml of anhydrousTHF, the medium is heated under reflux and 0.5 ml of borane-dimethylsulfide is added thereto and the medium is heated under reflux for 4hours. The medium is cooled to 0-5° C. and 7 ml of methanol arecarefully added thereto. After 5 minutes, the medium is heated underreflux for 30 minutes, the solvent is evaporated off, the residue istaken up in the water/ammonia=1/1 mixture, the medium is extracted withethyl acetate, the two phases are separated and the organic phase iswashed with water. The medium is dried over sodium sulfate and thesolvent is evaporated off under reduced pressure. The crudecrystallization product is purified in 2-propyl ether. 0.37 g of thetitle product is obtained.

m.p. 154-156° C.

1c)1-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

350 mg (0.8 mmol) of the product of the preceding step are dissolved in10 ml of acetic acid, 1 ml of sulfuric acid at 96% is added thereto andthe medium is heated at 80° C. for 2 hours. The medium is cooled,concentrated NH₄OH is added thereto and the medium is extracted withethyl acetate. The medium is washed with water, dried and evaporatedunder reduced pressure. The title compound is obtained. Thehydrochloride is prepared with the aid of a solution of 2-propanolsaturated with hydrochloric acid.

m.p. (hydrochloride) 264-266° C.

EXAMPLE 21-[2-(2,3-Dihydro-1H-inden-5-yl)ethyl]-4-[3-trifluoromethylphenyl]-1,2,3,6-tetrahydropyridineand its hydrochloride

The product obtained in Preparation 3 is dissolved in 17 ml of butanol.0.84 g (3.2 mol) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 0.9 g (6.5mmol) of potassium carbonate are added thereto and the medium is heatedunder reflux for 5 hours. The solvent is evaporated off and the residueis washed with water. It is extracted with methylene chloride, theorganic phase is dried and the solvent is evaporated off under reducedpressure. The residue is purified on a silica gel column, eluting with acyclohexane/ethyl acetate=8/2 mixture. The title compound is obtained.The hydrochloride is prepared with the aid of 2-propanol saturated withhydrochloric acid.

m.p. (hydrochloride) 252-255° C.

EXAMPLE 31-[2-(5,6,7,8-Tetrahydronaphthalen-2-yl)ethyl]-4-[3-trifluoromethylphenyl]-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 2 but using theproduct of Preparation 4 instead of the product of Preparation 3, thetitle compounds are obtained.

m.p. (hydrochloride): 263-267° C.

EXAMPLE 41-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, the titlecompounds are obtained.

m.p. (hydrochloride): 254-258° C.

EXAMPLE 51-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(6-trifluoromethylpyrid-2-yl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using4-(6-trifluoromethylpyrid-2-yl)-1,2,3,6-tetrahydropyridine instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, the titlecompounds are obtained.

m.p. (hydrochloride): 264-267° C.

EXAMPLE 61-[3-(2,3-Dihydro-1H-inden-5-yl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 2 but using theproduct of Preparation 5 instead of the product of Preparation 3, thetitle compounds are obtained.

m.p. (hydrochloride): 192-195° C.

EXAMPLE 71-[4-(2,3-Dihydro-1H-inden-5-yl)butyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 2 but using theproduct of Preparation 6 instead of the product of Preparation 3, thetitle compounds are obtained.

m.p. (hydrochloride): 198-200° C.

EXAMPLE 81-[2-(Fluoren-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 2 but using theproduct of Preparation 7 instead of the product of Preparation 3, thetitle compounds are obtained.

m.p. (hydrochloride): 285-287° C.

EXAMPLE 91-[2-(9,10-Dihydrophenanthren-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 2 but using theproduct of Preparation 8 instead of the product of Preparation 3, thetitle compounds are obtained.

m.p. (hydrochloride): 256-258° C.

EXAMPLE 101-[2-(2,3-Dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine1-oxide

0.27 g of m-chloroperbenzoic acid is added to a solution of 0.47 g (1.1mmol) of1-[2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(6-trifluoromethylpyrid-2-yl)-1,2,3,6-tetrahydropyridinein 40 ml of methylene chloride at the temperature of 0-5° C. The mediumis kept stirring at 0-5° C. for two hours, washed with a saturatedaqueous sodium bicarbonate solution and the two phases are separated.The organic phase is dried, filtered and evaporated under reducedpressure. The medium is purified by chromatography, eluting with amethanol/ethyl acetate=1/1 mixture and the title product is obtained.

m.p.: 116-117° C.

EXAMPLE 111-[2-(Fluoren-3-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using theproduct of Preparation 9 instead of the product of Preparation 2, thetitle compounds are obtained.

m.p. (hydrochloride): 238-240° C.

EXAMPLE 121-[2-(2,3-Dihydro-1H-cyclopenta[a]naphthalen-8-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using theproduct of Preparation 10 instead of the product of Preparation 2, thetitle compounds are obtained.

m.p. (hydrochloride): 212-213° C.

EXAMPLE 131-[2-(5,6,7,8-Tetrahydrophenanthren-3-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using theproduct of Preparation 11 instead of the product of Preparation 2, thetitle compounds are obtained.

m.p. (hydrochloride): 222-224° C.

EXAMPLE 141-[2-(5,6,7,8-Tetrahydroanthracen-2-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the procedure as described in Example 1 but using theproduct of Preparation 12 instead of the product of Preparation 2, thetitle compounds are obtained.

m.p. (hydrochloride): 252-253° C.

1. A compound of formula (I):

in which X represents N or CH; R₁ represents a hydrogen or halogen atomor a CF₃ group; n is an integer from 1 to 5; and A represents a group offormula (a) to (d):

 in which m is 1 or 2; or a salt, solvate or N-oxide thereof.
 2. Thecompound according to claim 1, where n is
 1. 3. The compound accordingto claim 1, where R₁ is a CF₃ group.
 4. The compound according to claim1, where X is CH and R₁ is at the 3-position of the benzene.
 5. Thecompound according to claim 1, where X is N and the pyridine issubstituted at the 2,6-positions.
 6. The compound according to claim 1,selected from the group consisting of:1-[2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(2,3-dihydro-1H-inden-5-yl)ethyl]-4-[3-trifluoromethylphenyl]-1,2,3,6-tetrahydropyridine;1-[2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl]-4-[3-trifluoromethylphenyl]-1,2,3,6-tetrahydropyridine;1-[2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;1-[2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-4-(6-trifluoromethylpyrid-2-yl)-1,2,3,6-tetrahydropyridine;1-[3-(2,3-dihydro-1H-inden-5-yl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[4-(2,3-dihydro-1H-inden-5-yl)butyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(fluoren-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(9,10-dihydrophenanthren-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(2,3-dihydro-1H-cyclopenta[b]naphthalen-6-yl)ethyl]-(4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(fluoren-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(2,3-dihydro-1H-cyclopenta[a]naphthalen-8-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;1-[2-(5,6,7,8-tetrahydrophenanthren-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;and1-[2-(5,6,7,8-tetrahydroanthracen-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;or a salt, solvate or N-oxide thereof.
 7. A method for preparing acompound according to claim 1 comprising: (a) the reacting a compound offormula (II):

 with an acid compound of formula (III) or one of its functionalderivatives

 to form a compound of formula IV

(b) reducing the carbonyl group of the compound of formula (IV), to forma compound of formula V;

(c) dehydrating the compound of formula (V) wherein R₁, X, n and A inthe above formulae are as defined in claim
 1. 8. The compound accordingto claim 2 wherein R₁ is CF₃.
 9. The compound according to claim 2wherein X is CH and R₁ is at the 3-position of the benzene.
 10. Thecompound according to claim 3 wherein X is CH and R₁ is at the3-position of the benzene.
 11. The compound according to claim 8 whereinX is CH and R₁ is at the 3-position of the benzene.
 12. The compoundaccording to claim 2 wherein X is N and the pyridine is substituted atthe 2,6-positions.
 13. A compound according to claim 3 wherein X is Nand the pyridine is substituted at the 2,6-positions.
 14. Apharmaceutical composition comprising a pharmaceutically acceptableamount of the compound according to claim 1 and a pharmaceuticallyacceptable vehicle.
 15. A pharmaceutical composition comprising apharmaceutically acceptable amount of the compound according to claim 6and a pharmaceutically acceptable vehicle.
 16. A pharmaceuticalcomposition comprising a pharmaceutically acceptable amount of thecompound according to claim 11 and a pharmaceutically acceptablevehicie.
 17. A pharmaceutical composition according to claim 14containing from 0.001 to 100 mg of active ingredient.
 18. A method forproducing analgesia in a patient in need thereof comprisingadministering to said patient an analgesically effective amount of acompound according to claim
 1. 19. A method for producing analgesia in apatient in need thereof comprising administering to said patient ananalgesically effective amount of a compound according to claim
 6. 20. Amethod for producing analgesia in a patient in need thereof comprisingadministering to said patient an analgesically effective amount of acompound according to claim 11.